Despite advances and treatments in autoimmune disease, there remains an unmet need for safer and more efficacious treatments that are tailored to the individual patient. These advances cannot occur without significant advances in our knowledge and understanding of disease mechanisms. The overarching theme of our proposed Program is that since the tissue injury occurring in autoimmune disease is the end result of multiple and often redundant inflammatory pathways and mediators (cytokines); we believe that an anti-inflammatory approach that modulates multiple inflammatory mediators will be associated with greater clinical efficacy. We will seek agents with improved tolerability and a better safety profile than current therapeutic options. Towards this end, we propose two clinical trials, one in RA and the other in SLE. In RA, we propose a study of GTS-21. This agent activates the cholinergic anti-inflammatory pathway by engaging the alpha 7 nicotinic receptor resulting in reduced production of inflammatory cytokines. The second trial is a study of ajulemic acid in SLE. This agent is a synthetic cannaboid which is non psychotropic and which possesses multiple anti-inflammatory properties. Each of these studies will evaluate the efficacy of the studied agent and each is accompanied by mechanistic studies to determine the biologic effects of the therapeutic intervention. Each is also designed to assess potential biomarkers of response. To accomplish these studies, we have assembled a consortium of outstanding collaborating sites to form The Feinstein Institute for Medical Research Center for Clinical Research in Autoimmune Disease. This Center will strive to conduct collaborative innovative clinical trials that will 1) promote improved patient outcomes through control of inflammatory disease and a reduction of organ damage and dysfunction, 2) result in a better understanding of the pathogenesis of autoimmune diseases and mechanisms for therapeutic responses, 3) lead to a personalized medicine approach to treatment of autoimmune disease 4) evaluate agents that do not cause clinically significant immunosuppression and 5) conduct collaborative innovative clinical trials that would not be pursued by the pharmaceutical industry.